Antihemorrhagic compound



Patented Oct. 5, 1943 AN'rmEMQRBHAGIC COMPOUND Max Tishler'," 'Rahway,

' Wendler, Ann Arbor,

N. J., and Norman L. Mich, assignors to Merck & Co. Inc., Rahway, N. J.', a corporation of New v No Drawing, Original Serial'No; 328,161. Di

application April 5, 1940, vided and this application A i'lg us fll, 1942, Serial No. 453,283. In Canada 7 December 3 1, 1940 51,; i Claims. (o1. 260-396) This is a division of co-pending application Ser. No. 328,161, one April 5, 1940, for Antihemorrhag'ic compound? v This invention relate to antihemorrhag'io sub? stances, especially such as'those that may be derived from by-products ofrrvan'ous processesior the synthesis of vitamin'Ki, and to theirisola tion'; and to methods of converting such lay-products tovitaminK1. j a

Recently developed method's 'for the synthesis of vitamin K1 'involve, in themain, reaction be tween naphthoquinones and phytol; fin appropri ately'reactive forms; appropriately adapted; 'i Inj many such cases, it has been found'that in addition to themainobjective of the process i.e., the. synthetic production of vitaminK1 per se, certain hitherto unknown and unsuspected products may,

be formed, which the applicant has found can beJ isolated by proper methods applied by him to the, mother liquors of such vitamin K1 synthetic. processes. Such isolation, products have been chemically diilierentiate'd from the known vitamin K1, and have been found by appropriate biological assay to possess distinct antihemorrhagic activity.

Thus, in a; typicalexample forthe synthesis of vitamin K1 according to the method which Fieser described in the Journalofthe American Chemical Society 6l, 3467-."(1939), phytol isgreactedi' with 2 methyl lgi naphthohydroquinone V in "di oxanein the presence'offoxalic' acid "as a catalyst. In addition to the .dihydro vitamin K1 (Z-methyl 3-phytyl-1,4 naphthohydroquinone) produced by this methodjof 'Fieser ii'. -e.,.the dihydro compound which is later to be oxidizedto vitamin K1,; it has now been'ifound by the applicant that, among' the by-products formed in-this reaction is' a product? which may be isolated as a distinct chemical entity possessing antihemorrhagic activity. V

According to the method of Fieser (supra); the synthetic process for producing dihydro vitamin K1 is'conducted aboutas follows? A mixture of 10'gms; of 2-rnethyl-1,4naphthohydroquinone, 2.96 gmsfof phytol, 2.3- gms. of anhydrous oxalic acid, and 30 cc. of dioxahe is maintained at75 C1 for" 34 hours.' At the end per cent sodium hydrosuliite. ether layer is separated and washed with 2 per cent aqueous potassium hydroxide and sodium hydrosulfite until the aqueous extracts are no I 10 isolating and producing theynew compound whichi' ajparticular objective of the instant application may be carried out by the following steps,l. whieh are given for exemplificati'ont After the e'synthesized dihydro vitamin K1 has been removed by centrifugation, the residual Ji uQrwh c is; t e e ol u e h trateresulting from, that centrifuging; is then shakenwithpa 35 per-cent solution'of potassium hydroxide in: methanol (made by dissolving 35 gms. offlpotassium'hydroxide in-25; cc. of water and then adding. sufiicient methanol to make a volume of 100 cc.) to which has been added small amounts of sodium hydrosulfite'until the alkaline extract is 'colorlesst This operation removes small= traces of-dihydrovitamin K1 retainedfby the petroleum ether.? 'Thepe'trole'umether "solu- I tion is then concentrated to; an oil, which is fractionated in high vacuo. A low boiling fraction comes ov'er below-"l00 C. which is a mixture of phytadiene and phytol. When "the inside temperature is about 140? C., a very pale yellow oil distills over which weighs about 0.6 gm. This pale yellow oilis the-'r'iew activeagent referredt'o above: It is a; somewhat mobile -liquid, having 'a refra'ctiveindex indicated by n 'i .5o95'and'the empirical formula 031114302.

Anal. calcd, forCs1H4sOz: C, 82-30;" H,

- Eo und: ,s2,53, s2.50, mam- ,1 0.30, 1e65,

. The newlproduct, thus isolated and characterized, is produced in 'relatively large quantities: I

during theigprparation: of vitamin.,K1 by such methods as described; It hasvitamin Ki activity. per:se, and willgserve as an intermediate for the productionfofvitaminfKi. r I In respect to the probable chemical identity; of;

this new product, the,followingstructur'es.have

PATENT OFFICE he; shakinggthe i appeared to be possible in view of a consideration of the reaction:

I. By direct etherification fcaoihn 3 5 7 I I! I l l! l H I cm" II. By cyclization of dihydro vitamin K1 due to presence of acids r t on A 15 IYCH; H 1 C s H III. By 1,2 addition V O, 1 I f} at W which. is not a. stnuctureg-anala i u to that of 60 vitamin. Km. =(2);;T he. absorption spectrum. of. monoethylether. of. Z-methyL-IA-naphthohsrdro-I quinone is quite diifereritfrom.thatf'oflthe new product} 1 StructureILwaseliminated by, theiiactithat the new' product is resistant to oxidation by'sil'ver nitrate orgold chloride. Structure II is a c'hro mane and chromanesiare' oxidized byv thesej re agents. 1 In addition; naphtho'tocopherol{has been.

synthesized by=treating vitaminfli with stan'nous chloride in a'mixtur of hydrochloric and acetic acid. Thetocophe'rol thus: formed-. does reduce silver nitrate and goldcl'ilorideiandthasfamem' tl'rely diflerent absorption'spectmmi item that of theriew'product; p Q

Structures III and IV are consistent with the following Iacts:

(1) The new, product forms a ketone derivative. (2) The new product brominates readily with the elimination of hydrogen bromide.

(3) The new product reacts with methyl magnesium iodide, using 2 moles of the reagent and, during the course of the reaction, one

" mole of methane is'formed. (111 can give methane because the CH2 group "adjacent to the quinone can enolize.)

5 M). The new product reacts with aluminum isopropylate to give a diol. This reagent is specific'for the reduction of ketone oxygen. Structure III is favored because: (1) The new product does not dehydrate when sub- "jected to? rather drastic conditions. It would be expected that a compound containing-a tertiary hydroxyl as is the case in would readily dehydrate. (2) In the reductionusing aluminum isopropylate -.-four: atoms of hydrogen are added. For four atoms of hydrogen to be used is possible only in the case of III. (3) The new 7 product brorninates very; .easily; forming hydrogen bromide-inthe process. It would be expected III would brominate much more readily in thiswayi than. IV. a

I Conversion of new productto vitamin K1: Two

grams ofuthe new product is' mixedki with 5' cc. of decalinand heatedtoboilingsfor 18 hours while arapidstream of nitrogeniis passedthmugh the mixture. Following the heating, the mixture is cpncentratejdjto dryness undemreduced: pressure and theresidue containing 2-methy1-3-phytyl- 1,4,-naphthoqu inone; issuspended in '50; cc. of methanol, A solution of 2 gm. oi-sodium hydro sulfite in..-.4,,cc. of watenisadded and .thewhole shaken for 15 minutes, The mixture is poured into. three volumes-0f. water, 120. cc. ofwether are added,.the mixture is shaken. andithe; ether layer is, sep'aratedi. The, ,e'tlinextract is. then washed i enu u solution c nt ni 2 r ent potassium hydroxide Qari'd. 2 per cent' sodium hy dro sulfite until allthe Zernethyl-1,4snaphthohy droquinone whichiwas formed: in the reaction is removed; "(About 200 mgm is obtained.) The. etlierfsolutionis concentrated to dryness invacuo using nitrogen and the residue taken upin cc. oi petroleum ether. The petroleum ether; solution 'isshal ren 'with Claisens alkali containing small amounts; of sodium hydrosulfite. The resultant 2"- me t hty'l- 3-phytyl-1,4-naphthohydroquinone goes into the alcohollc alkalinelayer (that is, the

I Claisenalkaliilayer). giving a" yellow solution.

Tins-extraction: with Claisens' alkali i continued untilthe extracts are colorless. (The petroleum ether layer contains unchanged starting mate rial. This was established by i'solatingit and identifying it by analysis and-refractive index.) The Claisenalkali extracts= arecombined and poured into. 4 volumes or water" slowly and: the resulting mixtureeextracted with 10 cc. of petroleum ether. The petroleum ether extract isseparated,,chilled, and the resultant 2-methyl-.3- phytyL-IA-naphthohydroquinoneis. removed. by

centrifuging and purified by I repeated washings with cold, petroleum ether.--This dihydro comthat certain modifications may be made by those skilled in the art without departing from the spirit and scope of the invention.

We claim: 1. Process of converting a. substance having the formula CH: i C:oHan

mm 2-methyl-3-phytyl-1,4-naphthoquinone, consisting of heating the said substance, whereby conversion is efiected.

2. Process of converting a substance havin the formula into 2-Inethy1-3-phyty1-1,4-naphthoquinone, consisting of heating the said substance in the presence of an inert solvent, whereby conversion is effected.

3. Process oi'converting a substance having the formula to 2-methyl-3-phytyl-1,4-naphthoquinone comprising the steps of mixing the said substance with an inert organic solvent, heating the resulting mixture in the presence of-nitrogen, drying the resulting mixture under reduced pressure, suspending the residue containing 2-methyl-3- phytyl-1,4 naphthoquinone in an inert organic liquid, treating the resulting suspension with an aqueous solution of sodium hydrosulfite, separating and purifying the resulting 2-methyl-3- phytyl-1,4-naphth0hydroquinone and converting it to 2-methyl-3-phytyl-1,4-naphthoquinone.

MAX TISHLER. NORMAN L. WENDLER. 

